Definition Local anaesthetic systemic toxicity (LAST) occurs when the plasma level of local anaesthetic is high enough to cause major interference with sodium channels outside of the intended area of action (nerve block). LAST is not only caused by blocking the sodium channel but is also due to effects on other ion channels on the cell membrane (i.e. potassium and calcium channels) as well as direct negative effects on mitochondrial metabolism.

High plasma levels of local anaesthetic agents may occur when administering the correct dose in the wrong place (i.e. unintended vascular injection; by rapid absorption from very vascular tissues) or the wrong dose (i.e. overdose).of LA is injected in the correct place In children LAST mainly manifests as CNS (seizures) or cardiovascular signs (ventricular arrhythmias or cardiac arrest) since the more subtle pretoxic signs or symptoms are not easily recognized under general anaesthesia or deep sedation.

Incidence The reported incidence of local anesthetic systemic toxicity (LAST) in infants and children is remarkably low.^1–3 Reports of vascular puncture does not always equate to LAST. Systemic toxicity requiring intervention is mostly confined to isolated case reports. Unintended vascular puncture is much more frequent but will rarely result in LAST if adequate precautions are taken.

Few cases have been reported in large prospective multicentre audits. A positive test dose on the other hand is largely dependant on the type of block performed and the age of the patient. In an audited cohort from the Pediatric Regional Anesthesia Network (PRAN) database comprising a total of 26,949 blocks using a test dose, there was a 0.21% incidence of positive test doses, almost all of which occurred during caudal or epidural placement (Evidence B3).³ There were no positive test doses in other blocks with the exception of one truncal block. Test doses were less frequently utilized in non-neuraxial blocks particularly those performed under ultrasound guidance.² An advantage of ultrasound is that the local anesthetic agent can be seen to spread outside the vessel.

An audit of 104,393 blocks placed in 91,701 patients at 20 institutions in the PRAN database for LAST revealed an incidence of 0.67:10,000 (95% CI 0.29–1.4:10,000).³ Only 7 cases of seizures⁴ or cardiac arrest ⁵ after bolus administration mainly in infants 1–5 months of age were recorded. A further 12 cases with continuous infusions had minor signs of toxicity that were resolved by stopping the infusion^{3 4} Precautions should therefore be taken whenever a bolus dose is administered especially on top of a background infusion.

Detection of LAST in children Detection, particularly in the more susceptible infants and neonates, is difficult. The majority of children are anaesthetised or sedated prior to placement of neuraxial or peripheral nerve block. General anaesthesia not only raises the threshold for LAST but also masks the classic early signs and symptoms (dizziness, somnolence, peri-oral tingling, tinnitus, metallic taste, visual disturbance). Under anaesthesia LAST manifests with ECG changes (ST segment changes, ventricular ectopy, ventricular tachycardia or ventricular fibrillation) and or signs of cardiovascular compromise (myocardial depression, reduced systemic vascular resistance).

CNS manifestations (convulsions and muscle twitching) are difficult to detect under anaesthesia but are more obvious postoperatively in those with continuous infusions of local anaesthetic agents. Loss of consciousness, respiratory depression (tachypnoea, dyspnoea, cyanosis) and or cardiovascular collapse (syncope palpitations) are other manifestations of toxicity seen with continuous infusions.

Prevention The risk for LAST is tied to the choice of local anaesthetic agent. Short-acting amide LA agents (e.g. carbocaine or lidocaine) are generally less toxic compared to long-acting LA.^5–7 Of the long-acting local anesthetics ropivacaine and levo-bupivacaine are preferable to bupivacaine in view of their lower cardiac toxicity profile.⁶ Bupivacaine tends to accumulate after 48hr of continuous infusion.

However no local anaesthetic is free from the risk. A 9-month-old infant developed LAST after an injection of 2-chloroprocaine (ester-type LA) into a paravertebral catheter.⁷ Despite 2-chloroprocaine’s rapid metabolism, being hydrolysed by plasma pseudo-choline esterases, the combination of an unusually high dose (28 mg/kg) and a likely direct intravascular injection contributed to producing LAST was noted in this report.

Performing a regional anaesthetic block in a vascular location is risky and may also predispose to LAST. Based on case reports, penile blocks in infants and children are the most common block associated with LAST.^{8 9} Yu et al described seven cases of LAST after penile blocks.⁸ After revising the technique by limiting the maximum dose of racemic bupivacaine to less than 1.25 mg/kg and by directing injections laterally, away from the central venous plexus at the base of the penis, no case of LAST occurred in 1.126 subsequent penile blocks.

Regardless of the local anaesthetic used strict adherence to dosing guidelines and avoiding conditions that predispose to toxicity (hypoxaemia, hypercarbia and acidosis) is important. Aspiration prior to injection and slow incremental injections (0.1–0.2 ml.kg) and the use of ultrasound are key to reducing the risk of LAST.

Management of LAST In the event of cardiovascular collapse or convulsions as a result of LAST, immediate basic life support should be instituted. Research has shown that implementing a checklist via a designated reader may be of benefit.¹⁰

The following management guidelines should be followed.^10–16

1. Stop administration of local anaesthetic and call for help

2. Immediate hyperventilation with 100% oxygen

3. Suppression of seizures if present (midazolam, thiopentone, propofol)

4. External cardiac massage in the presence of inadequate circulation cardiac arrest

5. Epinephrine 1 mcg.kg or 0.1 ml.kg epinephrine 1:1000 IV

6. Administration of 20% Intralipid 1.5 mL/kg intravenously over 1 minute. Follow immediately with an infusion at a rate of 0.25 ml/kg/min(ideal body weight)

N.B. Lipid emulsion in propofol should not be used in lieu of intralipid.

1. Continue chest compressions (lipid must circulate)

2. Repeat bolus every 3–5 minutes up to 3 mL/kg total dose until circulation is restored

3. Continue infusion until hemodynamic stability is restored.

4. Increase the rate to 0.5 mL/kg/min if BP deteriorates

5. A maximum total dose of 10–12 mL/kg in first 30 mins is recommended. Excessive lipid emulsion may lead to symptoms of ventilation perfusion (VQ) mismatch, hypersomnolence, metabolic acidosis with elevated lactate levels and hypertriglyceridaemia.

6. Continue monitoring 4–6h after CVS event; at least 2h after CNS event

7. Avoid vasopressin, calcium channel blockers, beta–blockers or other local anaesthetic agents.

8. If an adequate response is not achieved consider ECMO when available.

Multiple theories as to the mechanism of action of the lipid emulsion exist.^10–15 Intravenous lipid emulsion therapy provides a multimodal resuscitation benefit that includes both scavenging (e.g, the lipid shuttle) and non-scavenging components. The intravascular lipid compartment scavenges drug from organs susceptible to toxicity and accelerates redistribution out of cardiac tissue and brain to muscle where the drug is stored, and to the liver where its metabolism leads to detoxification, and later excreted. In addition, lipid exerts non-scavenging effects that include post-conditioning (via activation of pro-survival kinases) along with cardiotonic and vasoconstrictive benefits. These effects protect tissue from ischemic damage and increase tissue perfusion during recovery from toxicity.

Other mechanisms that have fallen from favour through lack of evidence include (i) at the mitochondrial level (interrupts fatty acid transport into cardiac mitochondria) and Intralipid supplies new energy (ii) activation calcium channels increasing intracellular calcium.

Conclusions

1. The risk for LAST in children is very low (approximately 6 per 100.000 blocks).

2. Adherence to guidelines for maximum acceptable dosage and use of apprpriate technique when performing pediatric regional anesthesia is important

3. Regardless of the local anesthetic agent used strict adherence to dosing guidelines and avoiding conditions that predispose to toxicity (hypoxemia, hypercarbia and acidosis) is important.

4. Aspiration prior to injection, slow incremental injections (0.1–0.2 ml/kg) and the use of ultrasound guidance are key to reducing the risk of LAST

5. The use of ultrasound guidance is likely to reduce the risk for LAST. The provider should visualize the needle tip at all times, observe adjacent vascular structures and see the spread of the local anesthetic solution being injected.

6. From a risk of LAST point of view, the use of racemic bupivacaine should be replaced by the less cardiotoxic alternatives ropivacaine or levo–bupivacaine when choosing to use long–acting local anesthetics.

7. Exercise caution when a bolus dose is administered especially on top of a continuous epidural infusion or a continuous infusion through a peripheral nerve catheter.

References

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2. Taenzer AH, Walker BJ, Bosenberg AT, Martin L, Suresh S, Polaner DM, Wolf C, Krane EJ. Asleep versus awake: does it matter?: Pediatric regional block complications by patient state: a report from the pediatric regional anesthesia network. Reg Anesth Pain Med 2014;39(4):279–83.

3. Walker BJ, Long JB, Sathyamoorthy M, Birstler J, Wolf C, Bosenberg AT, et al, Pediatric Regional Anesthesia Network Investigators. Complications in pediatric regional anesthesia: an analysis of more than 100,000 blocks from the pediatric regional anesthesia network. Anesthesiology 2018;129(4):721–32.

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7. Najafi N, Veyckemans F, DuMaine C, et al. Systemic toxicity following the use of 1% ropivacaine for pediatric penile nerve block. Reg Anesth Pain Med 2016;41:549–550.

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